scholarly journals Adaptation and Constraint in the Atypical Chemokine Receptor Family in Mammals

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Li Pan ◽  
Jianliang Lv ◽  
Zhongwang Zhang ◽  
Yongguang Zhang
Keyword(s):  
Ligand Binding ◽  
Chemokine Receptors ◽  
Homo Sapiens ◽  
Mammalian Species ◽  
Evolutionary Analysis ◽  
Amino Acid Residues ◽  
Mammal Species ◽  
And Function ◽  
G Protein Coupled ◽  
Receptor Family

Atypical chemokine receptors (ACKRs) are a subclass of G protein-coupled receptors characterized by promiscuity of ligand binding and an obvious inability to signal after ligand binding. Although some discoveries regarding this family in Homo sapiens and other species have been reported in some studies, the evolution and function of multiple ACKR in mammals have not yet been clearly understood. We performed an evolutionary analysis of ACKR genes (ACKR1, ACKR2, ACKR3, and ACKR4) in mammals. Ninety-two full-length ACKR genes from 27 mammal species were retrieved from the Genbank and Ensemble databases. Phylogenetic analysis showed that there were four well-conserved subfamilies in mammals. Synteny analysis revealed that ACKR genes formed conserved linkage groups with their adjacent genes across mammalian species, facilitating the identification of ACKRs in as yet unannotated genome datasets. Analysis of the site-specific profiles established by posterior probability revealed the positive-selection sites to be distributed mainly in the ligand binding region of ACKR1. This study highlights the molecular evolution of the ACKR gene family in mammals and identifies the critical amino acid residues likely to be relevant to ligand binding. Further experimental verification of these findings may provide valuable information regarding the ACKR’s biochemical and physiological functions.

scholarly journals QTY code enables design of detergent-free chemokine receptors that retain ligand-binding activities

2018 ◽  
Vol 115 (37) ◽  
pp. E8652-E8659 ◽  
Author(s):  
Shuguang Zhang ◽  
Fei Tao ◽  
Rui Qing ◽  
Hongzhi Tang ◽  
Michael Skuhersky ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Ligand Binding ◽  
Chemokine Receptors ◽  
Transmembrane Domain ◽  
Water Soluble ◽  
Helical Structures ◽  
Protein Gp41 ◽  
Hydrophobic Amino Acids ◽  
And Function ◽  
G Protein Coupled

Structure and function studies of membrane proteins, particularly G protein-coupled receptors and multipass transmembrane proteins, require detergents. We have devised a simple tool, the QTY code (glutamine, threonine, and tyrosine), for designing hydrophobic domains to become water soluble without detergents. Here we report using the QTY code to systematically replace the hydrophobic amino acids leucine, valine, isoleucine, and phenylalanine in the seven transmembrane α-helices of CCR5, CXCR4, CCR10, and CXCR7. We show that QTY code-designed chemokine receptor variants retain their thermostabilities, α-helical structures, and ligand-binding activities in buffer and 50% human serum. CCR5QTY, CXCR4QTY, and CXCR7QTY also bind to HIV coat protein gp41-120. Despite substantial transmembrane domain changes, the detergent-free QTY variants maintain stable structures and retain their ligand-binding activities. We believe the QTY code will be useful for designing water-soluble variants of membrane proteins and other water-insoluble aggregated proteins.

scholarly journals Characterization of the G protein-coupled receptor family SREB across fish evolution

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Timothy S. Breton ◽  
William G. B. Sampson ◽  
Benjamin Clifford ◽  
Anyssa M. Phaneuf ◽  
Ilze Smidt ◽  
...  
Keyword(s):  
G Protein ◽  
Genomic Structure ◽  
Integrated Approach ◽  
Orphan Receptor ◽  
Specific Gene ◽  
Testicular Development ◽  
Brain Expression ◽  
And Function ◽  
G Protein Coupled ◽  
Receptor Family

AbstractThe SREB (Super-conserved Receptors Expressed in Brain) family of G protein-coupled receptors is highly conserved across vertebrates and consists of three members: SREB1 (orphan receptor GPR27), SREB2 (GPR85), and SREB3 (GPR173). Ligands for these receptors are largely unknown or only recently identified, and functions for all three are still beginning to be understood, including roles in glucose homeostasis, neurogenesis, and hypothalamic control of reproduction. In addition to the brain, all three are expressed in gonads, but relatively few studies have focused on this, especially in non-mammalian models or in an integrated approach across the entire receptor family. The purpose of this study was to more fully characterize sreb genes in fish, using comparative genomics and gonadal expression analyses in five diverse ray-finned (Actinopterygii) species across evolution. Several unique characteristics were identified in fish, including: (1) a novel, fourth euteleost-specific gene (sreb3b or gpr173b) that likely emerged from a copy of sreb3 in a separate event after the teleost whole genome duplication, (2) sreb3a gene loss in Order Cyprinodontiformes, and (3) expression differences between a gar species and teleosts. Overall, gonadal patterns suggested an important role for all sreb genes in teleost testicular development, while gar were characterized by greater ovarian expression that may reflect similar roles to mammals. The novel sreb3b gene was also characterized by several unique features, including divergent but highly conserved amino acid positions, and elevated brain expression in puffer (Dichotomyctere nigroviridis) that more closely matched sreb2, not sreb3a. These results demonstrate that SREBs may differ among vertebrates in genomic structure and function, and more research is needed to better understand these roles in fish.

scholarly journals Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

2021 ◽  
Vol 8 ◽  
Author(s):  
Giuseppe Deganutti ◽  
Silvia Atanasio ◽  
Roxana-Maria Rujan ◽  
Patrick M. Sexton ◽  
Denise Wootten ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Approved Drugs ◽  
G Protein Coupled ◽  
Dynamic Docking ◽  
Receptor Family

Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity.

scholarly journals Expression of CCRL2 Inhibits Tumor Growth by Concentrating Chemerin and Inhibiting Neoangiogenesis

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5000
Author(s):  
Diana Al Delbany ◽  
Virginie Robert ◽  
Ingrid Dubois-Vedrenne ◽  
Annalisa Del Prete ◽  
Maxime Vernimmen ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Chemokine Receptors ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Cancer Models ◽  
The Family ◽  
G Protein Coupled ◽  
Mouse Cancer Models ◽  
Receptor Family

CCRL2 belongs to the G protein-coupled receptor family and is one of the three chemerin receptors. It is considered as a non-signaling receptor, presenting chemerin to cells expressing the functional chemerin receptor ChemR23/CMKLR1 and possibly GPR1. In the present work, we investigate the role played by CCRL2 in mouse cancer models. Loss of function of Ccrl2 accelerated the development of papillomas in a chemical model of skin carcinogenesis (DMBA/TPA), whereas the growth of B16 and LLC tumor cell grafts was delayed. Delayed tumor growth was also observed when B16 and LLC cells overexpress CCRL2, while knockout of Ccrl2 in tumor cells reversed the consequences of Ccrl2 knockout in the host. The phenotypes associated with CCRL2 gain or loss of function were largely abrogated by knocking out the chemerin or Cmklr1 genes. Cells harboring CCRL2 could concentrate bioactive chemerin and promote the activation of CMKLR1-expressing cells. A reduction of neoangiogenesis was observed in tumor grafts expressing CCRL2, mimicking the phenotype of chemerin-expressing tumors. This study demonstrates that CCRL2 shares functional similarities with the family of atypical chemokine receptors (ACKRs). Its expression by tumor cells can significantly tune the effects of the chemerin/CMKLR1 system and act as a negative regulator of tumorigenesis.

scholarly journals Estrogen receptors and function in the male reproductive system

2009 ◽  
Vol 53 (8) ◽  
pp. 923-933 ◽  
Author(s):  
Maria Fatima Magalhães Lazari ◽  
Thais Fabiana Gameiro Lucas ◽  
Fabiana Yasuhara ◽  
Gisele Renata Oliveira Gomes ◽  
Erica Rosanna Siu ◽  
...  
Keyword(s):  
Growth Factors ◽  
Estrogen Receptors ◽  
Reproductive System ◽  
Male Reproductive System ◽  
Estrogen Signaling ◽  
Nuclear Receptor Family ◽  
And Function ◽  
Rapid Signaling ◽  
G Protein Coupled ◽  
Receptor Family

A substantial advance in our understanding on the estrogen signaling occurred in the last decade. Estrogens interact with two receptors, ESR1 and ESR2, also known as ERα and ERβ, respectively. ESR1 and ESR2 belong to the nuclear receptor family of transcription factors. In addition to the well established transcriptional effects, estrogens can mediate rapid signaling, triggered within seconds or minutes. These rapid effects can be mediated by ESRs or the G protein-coupled estrogen receptor GPER, also known as GPR30. The effects of estrogen on cell proliferation, differentiation and apoptosis are often mediated by growth factors. The understanding of the cross-talk between androgen, estrogen and growth factors signaling pathways is therefore essential to understand the physiopathological mechanisms of estrogen action. In this review we focused on recent discoveries about the nature of the estrogen receptors, and on the signaling and function of estrogen in the male reproductive system.

scholarly journals Prostanoid Receptors: Structures, Properties, and Functions

1999 ◽  
Vol 79 (4) ◽  
pp. 1193-1226 ◽  
Author(s):  
Shuh Narumiya ◽  
Yukihiko Sugimoto ◽  
Fumitaka Ushikubi
Keyword(s):  
Signal Transduction ◽  
Ligand Binding ◽  
Cultured Cells ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Current Status ◽  
Amino Acid Residues ◽  
Prostanoid Receptors ◽  
Binding Properties ◽  
G Protein Coupled

Prostanoids are the cyclooxygenase metabolites of arachidonic acid and include prostaglandin (PG) D2, PGE2, PGF2α, PGI2, and thromboxne A2. They are synthesized and released upon cell stimulation and act on cells in the vicinity of their synthesis to exert their actions. Receptors mediating the actions of prostanoids were recently identified and cloned. They are G protein-coupled receptors with seven transmembrane domains. There are eight types and subtypes of prostanoid receptors that are encoded by different genes but as a whole constitute a subfamily in the superfamily of the rhodopsin-type receptors. Each of the receptors was expressed in cultured cells, and its ligand-binding properties and signal transduction pathways were characterized. Moreover, domains and amino acid residues conferring the specificities of ligand binding and signal transduction are being clarified. Information also is accumulating as to the distribution of these receptors in the body. It is also becoming clear for some types of receptors how expression of their genes is regulated. Furthermore, the gene for each of the eight types of prostanoid receptor has been disrupted, and mice deficient in each type of receptor are being examined to identify and assess the roles played by each receptor under various physiological and pathophysiological conditions. In this article, we summarize these findings and attempt to give an overview of the current status of research on the prostanoid receptors.

scholarly journals Novel evolutionary lineages of the invertebrate oxytocin/vasopressin superfamily peptides and their receptors in the common octopus (Octopus vulgaris)

2005 ◽  
Vol 387 (1) ◽  
pp. 85-91 ◽  
Author(s):  
Atsuhiro KANDA ◽  
Honoo SATAKE ◽  
Tsuyoshi KAWADA ◽  
Hiroyuki MINAKATA
Keyword(s):  
Xenopus Oocytes ◽  
Octopus Vulgaris ◽  
Amino Acid Residues ◽  
Peripheral Tissues ◽  
The Common ◽  
Common Octopus ◽  
The Difference ◽  
G Protein Coupled ◽  
Evolutionary Lineages ◽  
Receptor Family

The common octopus, Octopus vulgaris, is the first invertebrate species that was shown to possess two oxytocin/vasopressin (OT/VP) superfamily peptides, octopressin (OP) and cephalotocin (CT). Previously, we cloned a GPCR (G-protein-coupled receptor) specific to CT [CTR1 (CT receptor 1)]. In the present study, we have identified an additional CTR, CTR2, and a novel OP receptor, OPR. Both CTR2 and OPR include domains and motifs typical of GPCRs, and the intron– exon structures are in accord with those of OT/VP receptor genes. CTR2 and OPR expressed in Xenopus oocytes induced calcium-mediated inward chloride current in a CT- and OP-specific manner respectively. Several regions and residues, which are requisite for binding of the vertebrate OT/VP receptor family with their ligands, are highly conserved in CTRs, but not in OPR. These different sequences between CTRs and OPR, as well as the amino acid residues of OP and CT at positions 2–5, were presumed to play crucial roles in the binding selectivity to their receptors, whereas the difference in the polarity of OT/VP family peptide residues at position 8 confers OT and VP with the binding specificity in vertebrates. CTR2 mRNA was present in various peripheral tissues, and OPR mRNA was detected in both the nervous system and peripheral tissues. Our findings suggest that the CT and OP genes, similar to the OT/VP family, evolved through duplication, but the ligand–receptor selectivity were established through different evolutionary lineages from those of their vertebrate counterparts.

Chemokine sequestration by atypical chemokine receptors

2006 ◽  
Vol 34 (6) ◽  
pp. 1009-1013 ◽  
Author(s):  
C.A.H. Hansell ◽  
C.V. Simpson ◽  
R.J.B. Nibbs
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Trafficking ◽  
Leucocyte Migration ◽  
Acquired Immune Responses ◽  
G Protein Coupled ◽  
Receptor Family

Leucocyte migration is essential for robust immune and inflammatory responses, and plays a critical role in many human diseases. Chemokines, a family of small secreted protein chemoattractants, are of fundamental importance in this process, directing leucocyte trafficking by signalling through heptahelical G-protein-coupled receptors expressed by the migrating cells. However, several mammalian chemokine receptors, including D6 and CCX-CKR (ChemoCentryx chemokine receptor), do not fit existing models of chemokine receptor function, and do not even appear to signal in response to chemokine binding. Instead, these ‘atypical’ chemokine receptors are biochemically specialized for chemokine sequestration, acting to regulate chemokine bioavailability and thereby influence responses through signalling-competent chemokine receptors. This is of critical importance in vivo, as mice lacking D6 show exaggerated cutaneous inflammatory responses and an increased susceptibility to the development of skin cancer. CCX-CKR, on the other hand, is predicted to modulate homoeostatic lymphocyte and dendritic cell trafficking, key migratory events in acquired immune responses that are directed by CCX-CKR-binding chemokines. Thus studies on ‘atypical’ chemokine receptors are revealing functional and biochemical diversity within the chemokine receptor family and providing insights into novel mechanisms of chemokine regulation.

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